EFFECTS OF ANTIMALARIALS AND PROTEASE INHIBITORS ON PLASMODIAL HEMOZOIN PRODUCTION

Malarial hemozoin may play an important role as a target for antimalar ial drugs and in disease pathogenesis. A new assay for hemozoin was de veloped in which the hemozoin was separated from cells by filtration. Trophozoites have substantially more hemozoin than rings, but there ar e relatively small differences between chloroquine-sensitive and chlor oquine-resistant strains. The effects on hemozoin content of chloroqui ne and artemisinin, two antimalarial drugs, and E64 and Pepstatin A, t wo protease inhibitors, were measured. At concentrations at which hypo xanthine incorporation was unaffected, the hemozoin content of rings w as decreased by E64, but not by the other three compounds. Artemisinin and Pepstatin A also had little effect on the hemozoin content of tro phozoites. Chloroquine and E64 inhibited trophozoite hemozoin formatio n, but inhibited hypoxanthine uptake to a similar or greater extent. W hen either rings or trophozoites were exposed to several higher concen trations of chloroquine, hemozoin content was diminished, but signific antly less than hypoxanthine uptake. Various concentrations of E64, in contrast, inhibited hemozoin production by both rings and trophozoite s significantly more than hypoxanthine incorporation, suggesting that hemozoin production may be directly affected by E64.